Safety Study of Fluconazole in Combination With Flucytosine for the Treatment of Early Cryptococcal Infection (SToP-Crypto)

• ClinicalTrials.gov Identifier: NCT01562132
• Recruitment Status: Terminated
• First Posted: March 23, 2012
• Results First Posted: August 31, 2015
• Last Update Posted: August 31, 2015
• Sponsor: Yale University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Kenya Medical Research Institute; Bausch Health Americas, Inc.; University of Nairobi
• Information provided by (Responsible Party): Ana-Claire Meyer, Yale University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cryptococcal Infection Disseminated
• Interventions: Drug: Flucytosine and fluconazole; Drug: Fluconazole
• Enrollment: 6

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	5FC Plus Fluconazole	Fluconazole Alone
Arm/Group Description	Combination therapy with oral fluconazole and flucytosine Flucytosine and fluconazole: Flucytosine 100mg/kg/day in 4 divided doses orally for 14 days given in combination with fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily	Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
Period Title: Overall Study
Started	3	3
Completed	3	3
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		5FC Plus Fluconazole	Fluconazole Alone	Total
Arm/Group Description		Combination therapy with oral fluconazole and flucytosine Flucytosine and fluconazole: Flucytosine 100mg/kg/day in 4 divided doses orally for 14 days given in combination with fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily	Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily	Total of all reporting groups
Overall Number of Baseline Participants		3	3	6
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	3 participants	3 participants	6 participants
		36; (28 to 49)	31; (26 to 58)	33.5; (26 to 58)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	3 participants	6 participants
	Female	1 33.3%	1 33.3%	2 33.3%
	Male	2 66.7%	2 66.7%	4 66.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Kenya	Number Analyzed	3 participants	3 participants	6 participants
		3	3	6
CD4+ T-cell Count; Median (Full Range); Unit of measure: Cells/microliter
	Number Analyzed	3 participants	3 participants	6 participants
		22; (18 to 56)	13; (3 to 16)	17; (3 to 56)

Outcome Measures

1. Primary Outcome

Title	Survival at 12 Weeks
Description	[Not Specified]
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	5FC Plus Fluconazole	Fluconazole Alone
Arm/Group Description:	Combination therapy with oral fluconazole and flucytosine Flucytosine and fluconazole: Flucytosine 100mg/kg/day in 4 divided doses orally for 14 days given in combination with fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily	Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
Overall Number of Participants Analyzed	3	3
Measure Type: Number; Unit of Measure: participants
	2	2

2. Secondary Outcome

Title	Survival at 2 Weeks
Description	[Not Specified]
Time Frame	2 weeks

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Survival at 24 Weeks
Description	[Not Specified]
Time Frame	24 weeks

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Number of Individuals Who Develop Cryptococcal Meningitis
Description	Clinical meningitis AND at least one of the following: cryptococcal antigen in the cerebrospinal fluid (CSF), cryptococcal organisms on India Ink stain, or fungal culture of CSF. Clinical meningitis will be defined as: fever>39.0°C, AND; severe headache, AND At least one of the following: meningismus,; photophobia,; new onset seizure,; focal neurological deficit localizable to the central nervous system; papilledema; confusion, delirium, or decreased level of consciousness.
Time Frame	24 weeks

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Number of Individuals Who Develop Immune Reconstitution Inflammatory Syndrome Due to Cryptococcus
Description	Individuals who develop clinical meningitis without evidence of fungal, bacterial, or parasitic (e.g. malaria) organisms in the cerebrospinal fluid. Clinical meningitis will be defined as: fever>39.0°C, AND; severe headache, AND; At least one of the following:; meningismus,; photophobia,; new onset seizure,; focal neurological deficit localizable to the central nervous system; papilledema; confusion, delirium, or decreased level of consciousness.
Time Frame	24 weeks

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Achieve Targeted Recruitment, Retention and Adherence Rates
Description	[Not Specified]
Time Frame	24 weeks

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Proportion of Individuals Requiring Treatment Discontinuation
Description	[Not Specified]
Time Frame	4 weeks

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Proportion of Individuals Requiring Dose Reduction
Description	[Not Specified]
Time Frame	24 weeks

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Number of Individuals With Treatment Related Adverse Events
Description	[Not Specified]
Time Frame	24 weeks

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Number of Individuals With Treatment Related Serious Adverse Events
Description	[Not Specified]
Time Frame	24 weeks

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	Cryptococcal Meningitis-free Survival at 24 Weeks
Description	Clinical meningitis AND at least one of the following: cryptococcal antigen in the cerebrospinal fluid (CSF), cryptococcal organisms on India Ink stain, or fungal culture of CSF. Clinical meningitis will be defined as: fever>39.0°C, AND; severe headache, AND At least one of the following: meningismus,; photophobia,; new onset seizure,; focal neurological deficit localizable to the central nervous system; papilledema; confusion, delirium, or decreased level of consciousness.
Time Frame	24 weeks

Outcome Measure Data Not Reported

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	5FC Plus Fluconazole		Fluconazole Alone
Arm/Group Description	Combination therapy with oral fluconazole and flucytosine Flucytosine and fluconazole: Flucytosine 100mg/kg/day in 4 divided doses orally for 14 days given in combination with fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily		Fluconazole monotherapy Fluconazole: fluconazole 1200mg orally once daily for 14 days, followed by 800mg orally once daily for 8 weeks, followed by 200mg orally once daily
All-Cause Mortality
	5FC Plus Fluconazole		Fluconazole Alone
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	5FC Plus Fluconazole		Fluconazole Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0.00%)		0/3 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	5FC Plus Fluconazole		Fluconazole Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100.00%)		2/3 (66.67%)
Blood and lymphatic system disorders
Neutropenia † [1]	2/3 (66.67%)	2	1/3 (33.33%)	1
Gastrointestinal disorders
Nausea † [1]	0/3 (0.00%)	0	1/3 (33.33%)	1
Vomiting † [2]	0/3 (0.00%)	0	1/3 (33.33%)	1
General disorders
Unintentional Weight Loss † [2]	1/3 (33.33%)	1	0/3 (0.00%)	0
† Indicates events were collected by systematic assessment; [1] Grade 1; [2] Grade 2

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Ana-Claire Meyer
• Organization: Yale University
• Phone: 203-737-8372
• EMail: ana-claire.meyer@yale.edu

• Responsible Party: Ana-Claire Meyer, Yale University
• ClinicalTrials.gov Identifier: NCT01562132
• Other Study ID Numbers: R21NS077858-01 ( U.S. NIH Grant/Contract ); R21NS077858-01 ( U.S. NIH Grant/Contract )
• First Submitted: March 21, 2012
• First Posted: March 23, 2012
• Results First Submitted: July 31, 2015
• Results First Posted: August 31, 2015
• Last Update Posted: August 31, 2015